Both tails and the centromere targeting domain of CENP-A are required for centromere establishment

Logsdon, Glennis A.; Barrey, Evelyne J.; Bassett, Emily; DeNizio, Jamie E.; Guo, Lucie Y.; Panchenko, Tanya; Dawicki-McKenna, Jennine M.; Heun, Patrick; Black, Ben E.

doi:10.1083/jcb.201412011

Cited by 96 publications

(115 citation statements)

References 39 publications

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“…3A). Previous research showed that CENP-A Ser18 is phosphorylated in HeLa and U2OS cells (23,38), which we confirmed by mass spectrometry (data not shown). We then determined if the Cyclin E1/CDK2 kinase can phosphorylate GST-tagged full-length CENP-A in vitro .…”

Section: Resultssupporting

confidence: 88%

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

et al. 2017

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The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.

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Section: Resultssupporting

confidence: 88%

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

et al. 2017

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“…S1B,C), indicating that histones can be efficiently incorporated into chromatin at the LacO locus. Our results are in agreement with two recent reports that demonstrated that LacI-CENP-A is assembled into chromatin at or near LacO arrays using a similar system (Logsdon et al 2015;Tachiwana et al 2015). Therefore, using this LacO/I targeting system, the interaction between CENP-N and CENP-A chromatin can be analyzed.…”

Section: The Rg Loop Of Cenp-a Plays a Key Role In The Recruitment Ofsupporting

confidence: 81%

Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N

et al. 2015

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Specific recognition of centromere-specific histone variant CENP-A-containing chromatin by CENP-N is an essential process in the assembly of the kinetochore complex at centromeres prior to mammalian cell division. However, the mechanisms of CENP-N recruitment to centromeres/kinetochores remain unknown. Here, we show that a CENP-A-specific RG loop (Arg80/Gly81) plays an essential and dual regulatory role in this process. The RG loop assists the formation of a compact "ladder-like" structure of CENP-A chromatin, concealing the loop and thus impairing its role in recruiting CENP-N. Upon G1/S-phase transition, however, centromeric chromatin switches from the compact to an open state, enabling the now exposed RG loop to recruit CENP-N prior to cell division. Our results provide the first insights into the mechanisms by which the recruitment of CENP-N is regulated by the structural transitions between compaction and relaxation of centromeric chromatin during the cell cycle.

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“…The CATD in the context of the rest of histone H3 (H3 CATD ) is sufficient to bind HJURP and direct its deposition to centromeres (Black et al 2004; Black et al 2007; Hu et al 2011). CENP-A equivalent substitutions in this mutant (H3 CATD-Q68S ) significantly enhances its ability to interact with HJURP (Logsdon et al 2015; Yu et al 2015). Nevertheless, the H3 mutant containing Ser-68 without the CATD remains unable to bind to HJURP, clearly reinforcing the idea that CATD is the primary determinant for CENP-A deposition to centromeres (Logsdon et al 2015; Yu et al 2015).…”

Section: Cenp-a Posttranslational Modifications and Deposition At Cenmentioning

confidence: 99%

“…1) (Black et al 2004). Sequences in the amino and carboxyl termini are not required for CENP-A deposition and appropriate targeting, but are involved in exerting CENP-A function in building the centromere (Fachinetti et al 2013; Foltz et al 2009; Logsdon et al 2015). Likewise, while the CATD is important for targeting CENP-A to the centromere, the two amino acid “bulge” Arg-80 and Gly-81 in the structure contributes to CCAN recruitment (Sekulic et al 2010; Tachiwana et al 2011).…”

Section: An Overview Of Cenp-a Structure and Posttranslational Modifimentioning

confidence: 99%

“…Substitution of Ser-68 with the bulky glutamine or phosphomimetic glutamic acid in CENP-A abolishes HJURP interaction and prevents its localization to centromeres, whereas the S68A mutant shows a robust binding with HJURP (Logsdon et al 2015; Yu et al 2015). The CATD in the context of the rest of histone H3 (H3 CATD ) is sufficient to bind HJURP and direct its deposition to centromeres (Black et al 2004; Black et al 2007; Hu et al 2011).…”

Section: Cenp-a Posttranslational Modifications and Deposition At Cenmentioning

confidence: 99%

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Posttranslational modifications of CENP-A: marks of distinction

Srivastava

Foltz

2018

Chromosoma

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Centromeres are specialized chromosome domain that serve as the site for kinetochore assembly and microtubule attachment during cell division, to ensure proper segregation of chromosomes. In higher eukaryotes, the identity of active centromeres is marked by the presence of CENP-A (centromeric protein-A), a histone H3 variant. CENP-A forms a centromere-specific nucleosome that acts as a foundation for centromere assembly and function. The posttranslational modification (PTM) of histone proteins is a major mechanism regulating the function of chromatin. While a few CENP-A site-specific modifications are shared with histone H3, the majority are specific to CENP-A-containing nucleosomes, indicating that modification of these residues contribute to centromere-specific function. CENP-A undergoes posttranslational modifications including phosphorylation, acetylation, methylation, and ubiquitylation. Work from many laboratories have uncovered the importance of these CENP-A modifications in its deposition at centromeres, protein stability, and recruitment of the CCAN (constitutive centromere-associated network). Here, we discuss the PTMs of CENP-A and their biological relevance.

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Both tails and the centromere targeting domain of CENP-A are required for centromere establishment

Abstract: New roles for the N-terminal histone tail and folded core of CENP-A are revealed by monitoring early steps in centromere establishment.

Cited by 96 publications

References 39 publications

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N

Posttranslational modifications of CENP-A: marks of distinction

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